THE NEW ZEALAND MEDICAL JOURNAL

THE NEW ZEALAND
MEDICAL JOURNAL
Journal of the New Zealand Medical Association
ACE inhibitor fetopathy: a case series and survey of opinion
amongst New Zealand paediatricians, obstetricians,
neonatologists, and nephrologists
Maneesh Deva, Tonya Kara
Abstract
The use of ACE (angiotensin converting enzyme) inhibitors is contraindicated
throughout pregnancy due to potential adverse effects to the developing fetus
(fetopathy). Despite this, women continue to receive ACE inhibitors both in New
Zealand and overseas and large scale epidemiological studies have shown cases of
associated harm to infants.
We present three New Zealand infants with potential renal complications following in
utero ACE inhibitor exposure including hypertension, renal failure and death. We also
present data from an email-based survey of experience and opinion from relevant
New Zealand specialists on how to best counsel women of child-bearing age
regarding ACE inhibitors (quantitative and qualitative data). To our knowledge this is
the first data published on this subject in New Zealand.
ACE inhibitor exposure in pregnancy may result in potential renal, cardiac and limb
complications for the developing fetus. How best to counsel women regarding ACE
inhibitors and pregnancy remains an area for further discussion in New Zealand.
Cases
Angiotensin converting enzymes (ACE) inhibitors are useful and well tolerated drugs
used in the treatment of hypertension.1 Their use in pregnancy in New Zealand is now
contraindicated due to proven adverse fetal effects (fetopathy).2–6 These effects
include malformations following oligohydramnios (lung hypoplasia, ossification and
limb defects); direct renal complications (hypertension, renal failure) as well as
cardiac and central nervous malformations due to impaired uteroplacental blood
flow.7–9
Ongoing use of ACE inhibitors during pregnancy has been observed overseas and
remains difficult to prevent.10 Women are often not under specialist care early in their
pregnancy and there is a potential lack of clinician awareness of this
contraindication.11 Previously, it was thought that first trimester use of ACE inhibitors
was safe, however the large scale cohort study in 2006 by Cooper et al has shown that
first trimester exposure is associated with an increased rate of malformations and
ACE inhibitors should be avoided throughout pregnancy.2 Therefore adequate advice
and education should be considered prior to pregnancy to avoid this preventable
outcome in New Zealand.
We present three New Zealand infants with potential renal complications from inutero exposure to ACE inhibitors, including hypertension, renal failure and death.
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Infant 1
Infant 1 was born to 38-year-old Indian mother, gravida 5 para 1 (2 miscarriages, 1
stillborn at 20 weeks gestation). The pregnancy was complicated by pre-existing
hypertension and gestational diabetes (managed with diet control). The mother was
taking the ACE inhibitor cilazapril until 17 weeks gestation when the pregnancy was
diagnosed. At the 18-week ultrasound scan, bilateral echogenic kidneys were
documented, pulmonary hypoplasia and possibility of an absent bladder.
The family was counselled prior to delivery that the expected outcome was poor and
therefore dialysis would not be offered in New Zealand as discussed with the tertiary
paediatric renal service. Infant 1 delivered via ventouse following spontaneous
preterm delivery at 35 weeks gestation with shoulder dystocia.
Infant 1 required Neopuff resuscitation taking first gasp at 2 minutes with established
respirations at 15 minutes (APGARS 3, 4, 6, 8). The infant was macrosomic with a
birthweight of 4130g (far above 97th centile) without significant oedema. Infant 1 was
admitted to Neonatal Intensive Care with continuous positive pressure (CPAP)
respiratory support.
Initial blood gas was consistent with birth asphyxia (pH = 6.99, base excess = -14).
Infant 1 remained hypoglycaemic for the first 12 hours despite escalating IV dextrose
concentrations. Infant 1 remained anuric for the first 24 hours with initial urea of 5
mmol/L and creatinine of 126 mmol/L (normal maternal biochemistry). Day 2 renal
ultrasound scan sited an empty bladder, oedematous kidneys with ‘no functional renal
tissue’ (Figure 1).
Figure 1. Bilateral multicystic dysplastic kidneys with no renal parenchyma
identified
Ventilation was weaned to oxygen on day 4, but Infant 1 remained anuric with
escalating serum urea and creatinine levels (Figure 2). Calcium gluconate and per
rectum resonium was used given associated hyperkalaemia.
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Figure 2. Consistently rising renal biochemistry values following birth
On day 5 Infant 1 had bloody nasogastric aspirates and prolonged periods of
desaturation. Comfort care plans were made, umbilical lines removed and Infant 1
passed away in the presence of family.
Infant 2
Infant 2 was born to a 43-year-old New Zealand Māori women, G5 P3 (1 previous
termination). The women had hypertension noted previously in each of her previous
pregnancies and was subsequently diagnosed with a benign pituitary tumour secreting
ACTH (Cushing’s disease). This was removed and replaced with daily
hydrocortisone. The hypertension persisted post resection which was well controlled
with the angiotensin II blocker (2nd generation ACE inhibitor) candesartan.
The pregnancy was unplanned and unexpected and candesarten continued through the
first trimester. The 20 weeks gestation ultrasound scan showed oligohydramnios and
candesarten was discontinued. Subsequent ultrasound scans showed recovery in
amniotic fluid and a cardiac effusion seen at 22 weeks also resolved. The maternal
hypertension was controlled without further medications for the remainder of the
pregnancy.
Infant 2 was born following spontaneous rupture of membranes and subsequent
induction of labour at 36 weeks. Infant 2 was vigorous at birth, weighed 3275g and
did not require resuscitation (APGARS 9, 9, 10). After initial breast feeds, Infant 2
and mother were transferred to a local birthing centre. Within 6 hours respiratory
distress was noted and Infant 2 was admitted to Neonatal Intensive Care.
Infant 2 was found to have severe myocardial dysfunction with poorly contractile
ventricles seen on echocardiogram. Infant 2 was treated with prostaglandins,
dobutamine, nitric oxide, antibiotics and was intubated for 10 days in total. Initial
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blood pressures were noted to be surprisingly ‘easy to maintain’ and as subsequent
echocardiograms and overall condition improved, hypertension became evident (with
mean arterial pressure recordings above 90 mmHg). This was managed with oral
hydralazine at usual dosage.
During the admission, Infant 2 had normal renal ultrasound scans, urea and
electrolytes and it was postulated that in- utero hypertension may have caused the
initial severe cardiac dysfunction. Infant 2 was discharged from Neonatal Intensive
Care on day 15, full suckling feeds on hydralazine with home monitoring of blood
pressures.
Renin levels were later found to be elevated (9.3 ng/mL/hour) which is consistent
with renovascular malformation in utero exposure to angiotension II inhibition1.
Hydralazine was later changed to Amlodipine with sound growth and developmental
progress being made.
Infant 3
Infant 3 was born to an 18-year-old New Zealand European/Pakeha primip. The
mother had a transposition of the great arteries repair at day 10 and pulmonary
stenting procedure at age 10 years. From childhood she was treated with the ACE
inhibitor quinapril. It is not known whether her parents were counselled regarding
pregnancy when this was commenced, however she has no recollection of this being
discussed with her directly or before transfer to adult services.
The pregnancy was unplanned and diagnosed at 5 weeks gestation and quinapril was
appropriately discontinued. The mother had ongoing urinary tract infections and was
on nitrofurantoin as prophylaxis. She was also Group B streptococcus positive at 35
weeks gestation. The pregnancy was noted to have oligohydramnios at the 28 week
gestation scan which progressed to anhydramnios. Echogenic kidneys and intrauterine
growth restriction was also noted subsequent ultrasound scans. The infant had normal
amniocentesis karyotype and TORCH serology. The parents had normal renal
ultrasound scans.
Infant 3 delivered following spontaneous labour via forceps assisted vaginal delivery
at term. The infant was vigorous (APGARS 7, 9, 9) and symmetrically growth
restricted (birthweight = 2005g) with normal male genitalia. The baby received CPAP
resuscitation and was intubated for increasing respiratory distress.
Initial chest radiograph revealed a small pneumomediastinum and pneumothorax
which resolved without intervention. A single dose of surfactant was given and the
infant was extubated on day 2. A widely splayed sagittal suture was noted- a feature
consistent with in utero ACE exposure.7,8 Urine output was seen within the first 24
hours however, serum urea and creatinine climbed (peak day 4 = 278 mmol/L).
Renal ultrasound scans showed small dysplastic kidneys with small cortical cysts.
Infant 3 commenced suckling feeds within the first week and was discharged on day
9. There was no hypertension during the admission. Oral sodium supplements were
required for persistent hyponatraemia and Kindergen (low protein) formula was used
to supplement feeds breast feeds. Infant 3 was readmitted to Neonatal Intensive Care
for three days for a calcium level of 3.6 which normalized with intravenous
pamidronate and fluids.
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Following discharge Infant 3 had a normal micturating cystourethrogram. Infant 3’s
weight remained low (5th centile) and nasogastric feeds were commenced. At the age
of 8 months a gastrostomy and Tenckhoff catheter was inserted to commence daily
dialysis. Weight gains improved further and work up commenced for transplantation
as urine output gradually declined.
At the age of 22 months Infant 3 received a deceased donor kidney and has been
making satisfactory progress post transplantation.
Discussion
ACE inhibitor fetopathy is a recognised clinical syndrome consisting of several
possible malformations following in utero exposure to ACE inhibitors and
angiotensin II blockers. These features consist of renal tubular dysplasia, anuria
oligohydramnios, growth retardation, hypocalvaria (including widely splayed suture
lines) and hypertension.7,8 These features, as seen in animal models, are thought to be
related to fetal hypotension during critical times of fetal development.9
Isolating and attributing the outcomes of the infants presented to only ACE inhibitor
exposure is not possible and certainly there has been wide phenotypic variation
reported following in utero ACE inhibitor exposure.12 Infant 1 was macrosomic and
clearly affected by maternal diabetes.
Infant 2’s mother was of advanced maternal age and Infant 3’s mother was also on
Nitrofurantoin (Category B pregnancy drug: probably safe, but concerns13) and had
multiple infections. Three of the mothers also had hypertension which itself has been
linked to complications during labour.14
This is also reflective of debate on this subject as safety data regarding the use of
ACE inhibitors stemmed from analyses of case reports which are clouded by
confounding factors.15,16 Only recently, following large cohort studies the strength of
this contradiction has increased.
The study by Cooper et al (2006) has been the most notable to date, quoting increased
risk of malformation rates with risk ratios ranging from 7.2 (central nervous system
and cardiovascular) to 9.32 (renal complications) with large confidence intervals
given the overall low incidence of these events (less than 1 per thousand live births).2
Locally, Medsafe New Zealand currently advises avoidance of ACE inhibitors
throughout pregnancy4–6 and to our knowledge, this is the first report on this subject
in New Zealand.
The three infants presented all had renal complications that are consistent with in
utero ACE inhibitor exposure and therefore are potentially avoidable. Reducing this
occurrence in New Zealand infants remains difficult for several reasons which these
cases highlight.
Many women may not be aware of pregnancy (and some may not be anticipating this
possibility) who are taking ACE inhibitors. Infant 2 and 3’s mothers were of advanced
in maternal age (38, 43) and pregnancy was not expected. Infant 2 followed from an
unplanned pregnancy which is not uncommon in the New Zealand population and has
been previously reported at 31%18 and worldwide at 38% of all live births.19
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As the indications for ACE inhibitors grow, heightened awareness will be required to
avoid inadvertent exposures.
Inadequacy of pregnancy counselling to potential mothers on ACE inhibitors has been
observed overseas and will be prevalent to some extent in New Zealand.11 Lack of
clinician awareness, lack of patient awareness and optimal timing of pregnancy
counselling are important considerations.
To explore the experience and current opinion of pregnancies potentially affected by
ACE inhibitors amongst New Zealand specialists we conducted a brief anonymous,
email based survey sent to paediatricians, neonataologists, maternal- fetal medicine
obstetricians and nephrologists.
Survey
Aims
To gather the opinion both quantitatively and qualitatively on the use of ACE
inhibitors during pregnancy by relevant hospital-based specialists in New Zealand
(paediatricians, neonatologists, maternal- fetal medicine obstetricians and
nephrologists).
Methods
We constructed a brief (<1 minute completion time) email-based survey with a short
introductory statement on the subject.20 The email was sent via the paediatric society
web server, perinatal society webserver and to maternal fetal medicine and
nephrology colleagues in New Zealand.
Results
Q1 identifying survey participants
The majority of the responses were from paediatricians (52/79 responses, 65%) with
the remainder of the responses made up from neonatologists (11), obstetricians (8)
and other physicians including nephrologists (8) (Figure 3).
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Figure 3. Survey participants
Survey Participants
9%
1%
paediatrician (52/79)
10%
neonatologist (11/79)
obstetrician/
gynaecologist (8/79)
other (7/79)
14%
renal physician
(1/79)
66%
Q 2,3—Do you have experience with a pregnancy which has had ACE inhibitor
exposure? What was the outcome/s?
Twenty-seven responses stated they had experience with a pregnancy which had
antenatal ACE inhibitor exposure. Of this, 14 out of 27 (52%) responses stated that
the neonate was affected as a result of ACE exposure, with 3 out 27 (11%) resulting
in fetal/ neonatal demise.
Q4. When is the best time to counsel women on ACE inhibitors?—
Nearly half of all responses indicated that at the time an ACE inhibitor is first
commenced is the best time to counsel regarding pregnancy. In addition two
responses commented that all of these times are appropriate (Figure 4).
Q5. Who is best placed to counsel women on ACE inhibitors?
Most responses either suggested the prescribing practitioner (26/ 72, 36%) or the
general practitioner (25/72, 35%) (Figure 5). A small number of responses suggested
that the LMC/ midwife would be best placed to do this (2 responses).
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Figure 4. When is the best time to counsel women on ACE inhibitors?
When is the best time to counsel women on ACE inhibitors?
when first commenced on an ACE
inhibitor
48
When of child bearing age
30
When planning to become
pregnant
26
When pregnancy is confirmed
7
During 1st antenatal visit
5
0
10
20
30
40
50
60
percentage
Figure 5. Who is best placed to counsel women on ACE inhibitors
Who is best placed to counsel women on ACE inhibitors?
the prescriber (26/61)
general practitioner
(25/61)
obstetrician (5/61)
physician (3/61)
LMC/midwife (2/61)
0
5
10
15
20
25
30
35
40
45
50
percentage
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In addition, three responses were thankful in alerting this to their attention as they
were not aware of this potential problem in pregnancy. Similar comments also stated
that the use of ACE inhibitors in pregnancy is underappreciated.
Discussion
The survey was limited by its nature and is by no means a useful estimation of the
true frequency of fetuses affected by ACE inhibitors in New Zealand. The
denominator was unknown and due to its anonymous nature, there is also the
possibility to have duplication of cases experienced by respondents. In New Zealand
PHARMAC reports well over a million ACE inhibitor prescriptions are filled per year
with an unknown, but potentially large number, to women of child bearing ages.21
The opinions of how best to deal with this potential problem in pregnancy highlights
several issues such as prescriber responsibility, timely pregnancy counselling and
clinician practice scope.
The general practitioner or prescriber was thought to be the most appropriate person
placed to counsel women by the majority of our survey responses. The difficulty in
keeping up to date of current best practice is an ongoing challenge for clinicians, not
helped by previous safety claims in the first trimester.11
A smaller group responded that the obstetrician or midwife (8/72, 11%) are better
placed to do so. The potential pitfalls of this approach are highlighted by the cases
presented in that the pregnancy may not be diagnosed for several weeks to months.
Another wider issue also exists of assigning (or assuming) responsibility by other
healthcare colleagues. This is most particularly pertinent in the care of pregnant
women where the sharing of care may take place between LMC, GPs and hospital
specialists.
The best time to counsel women remains another difficult area. Women may have
been commenced on ACE inhibitors years prior (such as infant 3’s mother) and
pregnancy counselling may not be appropriate, ideal or long lasting. Although 35%
(26/74) of responses suggested the best time would be at the time of planning a
pregnancy, in many situations the pregnancy may be unplanned18.
Furthermore, 12/74 stated the best time would be once pregnancy was confirmed or at
the first antenatal visit. This may reflect a slightly differing knowledge base of
pregnancy that our responders, primarily paediatricians, have towards pregnancy. This
was reinforced by the three comments received thanking our study for raising
awareness of this issue as they were previously unaware.
Our results suggest there is a range of opinion amongst our survey participants
reflecting differing experience and awareness. Heightened awareness by all health
care professionals involved in the use of ACE inhibitors is a good basis to reduce this
avoidable occurrence.
As the indications for ACE inhibitors grow, the challenges discussed will continue to
evolve. Although we only surveyed consultant specialists in our survey, similar
questions and opinions will be equally valuable and valid from LMCs, GPs,
pharmacists and legislators.
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Conclusion
In New Zealand we present three infants with potential renal complications from in
utero exposure to angiotensin converting enzyme (ACE) inhibitors, including
hypertension, renal failure and death. ACE inhibitors remain contraindicated
throughout pregnancy and to our knowledge this is the first data published on this
subject in New Zealand.
How best to counsel women regarding ACE inhibitors and pregnancy remains an area
for further discussion in New Zealand. From a paediatric point of view we need to
take into account that a drug may be started at an early age and remember to counsel
appropriately once the patient reaches an appropriate age.
Competing interests: None known.
Author information: Maneesh Deva, Advanced Paediatric Trainee (General
Paediatric); Tonya Kara, Project Supervisor and Paediatric Nephrologist;
Starship Children’s Hospital, Auckland
Acknowledgements: I thank the Children’s Research Centre at Starship Children’s
Hospital for their additional support as well as Dr Emily Chang.
Correspondence: Dr Maneesh Deva, Starship Children's Health, Private Bag 92024,
Auckland 1142, New Zealand. Email: [email protected]
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